A New Era: Treating Negative Symptoms in Schizophrenia

Pictured: Scan of human brain /iStock, MyndziakVideo

Pictured: Scan of human brain /iStock, MyndziakVideo

The anticipated New Drug Application for Karuna Therapeutics’ schizophrenia candidate, KarXT (xanomeline-trospium), is creating hype in a space that hasn’t seen much progress in half a century.

One reason for the excitement is that the drug may treat the negative symptoms of the disease, such as social withdrawal, lack of motivation and apathy toward normal interests. Currently approved schizophrenia treatments instead focus on the disorder’s positive symptoms relating to psychosis.

Experts caution, however, that KarXT was not specifically tested for its effects on negative symptoms, so its influence on them requires further proof.

Meanwhile, Acadia Pharmaceuticals is specifically targeting negative symptoms with pimavanserin, a drug that acts on two receptors in the serotonin family.

While positive symptoms such as delusions and paranoia are most commonly associated with schizophrenia, experts agree that treating negative symptoms is instrumental to a holistic therapeutic plan.

“If you’ve got significant negative symptoms, you’re going to have a bad outcome because you don’t do the things you’re able to do,” Philip Harvey, professor of psychiatry and behavioral sciences at the University of Miami Miller School of Medicine, told BioSpace.

A Schism of the Mind

Schizophrenia literally means schism in mind, Christoph Correll, professor of psychiatry and molecular medicine at The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, told BioSpace. “There is a disconnect between thinking, feeling, wanting and acting.” This dysconnectivity is very hard to reintegrate with just one medication because of the need to target different neurotransmitter systems, he added.

Christoph Correll_courtesy of Donald and Barbara Zucker School of Medicine at Hofstra/Northwell,
Christoph Correll

Correll said another challenge is that there can be either too much or too little dopamine in the brain. Too much dopamine causes psychosis, while too little causes negative cognitive symptoms. This leads to what Correll called a seesaw effect.

And this problem goes beyond dopamine. “It’s basically an excitation-inhibition problem that involves GABA and glutamate—the break in the system and the gas pedal in the system,” Correll said. “Harnessing those has been very difficult.”

The first treatments for schizophrenia focused on positive symptoms, largely because of chance, Harvey said. “We accidentally discovered drugs that treat positive symptoms about 60 or 70 years ago, and as a consequence, the treatment of schizophrenia has always focused on that.”.

Chlorpromazine, for example, became the first widely used drug for schizophrenia in the 1950s when French scientist Henri Laborit discovered its psychological effects while seeking a way to reduce surgical shock. 

Though positive and negative symptoms are probably linked at some level, Harvey said they clearly require different interventions.

“Antipsychotic medications don’t do anything for negative symptoms or cognitive impairments.”

KarXT May Treat Negative Symptoms

An investigational M1/M4-preferring muscarinic agonist, KarXT has amassed positive data in three registrational trials. Karuna expects to submit the NDA by mid-2023 and, if approved, KarXT would be the first new class of medicine for schizophrenia in more than 50 years, Karuna founder and Chief Operating Officer Andrew Miller told BioSpace.

KarXT has shown the potential to treat both the positive and negative symptoms of schizophrenia, as measured by the Positive and Negative Syndrome Scale (PANSS). Miller said there seems to be a beneficial effect on negative symptoms across the registrational EMERGENT-1, 2 and 3 studies but added that the design of the studies was more focused on positive symptoms.

“I think the benefits that we’ve seen across negative symptom endpoints, which were all statistically significant in EMERGENT-1 and -2 . . . reinforce the idea that with this pharmacology, we may have benefits that are broader than simply effects in psychosis,” he said.

Correll, however, said there are currently no data to suggest that KarXT effectively treats primary negative symptoms. To accurately measure the effects on negative symptoms, he said the study would need a clean baseline, with no depression, motor or positive symptoms present. “When you improve any of those . . . you get a secondary spillover effect into negative symptoms. So, you can’t deduce anything from the acute studies Karuna has done.”

A More Direct Approach

To specifically target schizophrenia’s negative symptoms, Acadia’s pimavanserin blocks two receptors in the serotonin family: 5-HT2A and, to a lesser extent, 5-HT2C. In so doing, it indirectly influences circuits related to GABA, glutamate and dopamine, Dragana Bugarski-Kirola, vice president of clinical research at Acadia, told BioSpace.

Dragana Bugarski-Kirola_courtesy of Acadia
Dragana Bugarski-Kirola

“That leads to an action that’s softer and gentler,” Bugarski-Kirola said. “More importantly, it is very selective just for two serotonin receptors, and by that, I mean that it has absolutely no side effects.” This differs from antipsychotics, including KarXT, which have off-target side effects, she said.

In a Phase II study of adult schizophrenia patients with predominantly negative symptoms, pimavanserin added to existing regimens of antipsychotics led to significant improvements versus placebo on the 16-item Negative Symptom Assessment (NSA-16).

“It does somehow seem like adding an additional compound that blocks 5-HT2A has an incremental benefit,” said Harvey, who is not involved in either Acadia or Karuna’s studies.

Correll, who has been an adviser to Acadia and Karuna but was not involved in their studies, said pimavanserin’s mechanism of action might be a smart way of targeting the system from different angles.

If pimavanserin has a positive Phase III trial, Correll said Acadia would be first to market for negative symptoms. 

KarXT “will almost certainly be approved,” Harvey said, but it will be approved for schizophrenia overall—not for negative symptoms specifically.

“You could use it to target any schizophrenia symptoms that you thought the drug would be effective for, like cognition or negative symptoms or psychosis,” he said. 

Aside from medication, Correll said psychotherapy could be helpful, and a healthy lifestyle is important.

“The problem is that what you need to do, you also need motivation for,” he said. “So hopefully, a medication that can help negative symptoms in isolation could then have a halo effect in these other activities that can help reconnect people to life.”

Heather McKenzie is a senior editor at BioSpace, focusing on neuroscience, oncology and gene therapy. You can reach her at heather.mckenzie@biospace.com. Follow her on LinkedIn: https://www.linkedin.com/in/heathermmckenzie/ and Twitter: @chicat08

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